Evidence for the significant role of immunoglobulin light chains in antigen recognition and selection in chronic lymphocytic leukemia.
We analyzed somatic hypermutation (SHM) patterns and secondary rearrangements involving the immunoglobulin (IG) light chain (LC) gene loci in 725 patients with chronic lymphocytic leukemia (CLL). Important differences regarding mutational load and targeting were identified in groups of sequences defined by IGKV/IGLV gene usage and/or K/LCDR3 features. Recurrent amino acid (AA) changes in the IGKV/IGLV sequences were observed in subsets of CLL cases with stereotyped B-cell receptors (BCRs), especially those expressing IGHV3-21/IGLV3-21 and IGHV4-34/IGKV2-30 BCRs. Comparison with CLL LC sequences carrying heterogeneous K/LCDR3s or non-CLL LC sequences revealed that distinct amino acid changes appear to be "CLL-biased." Finally, a significant proportion of CLL cases with monotypic LC expression were found to carry multiple potentially functional LC rearrangements, alluding to active, (auto)antigen-driven receptor editing. In conclusion, SHM targeting in CLL LCs is just as precise and, likely, functionally driven as in heavy chains. Secondary LC gene rearrangements and subset-biased mutations in CLL LC genes are strong indications that LCs are crucial in shaping the specificity of leukemic BCRs, in association with defined heavy chains. Therefore, CLL is characterized not only by stereotyped HCDR3 and heavy chains but, rather, by stereotyped BCRs involving both chains, which generate distinctive antigen-binding grooves.
Hadzidimitriou
Anastasia
A
Institute of Agrobiotechnology, Centre for Research and Technology, Thessaloniki, Greece.
Darzentas
Nikos
N
Murray
Fiona
F
Smilevska
Tanja
T
Arvaniti
Eleni
E
Tresoldi
Cristina
C
Tsaftaris
Athanasios
A
Laoutaris
Nikolaos
N
Anagnostopoulos
Achilles
A
Davi
Frederic
F
Ghia
Paolo
P
Rosenquist
Richard
R
Stamatopoulos
Kostas
K
Belessi
Chrysoula
C
D019943:Amino Acid Substitution / Q000235:genetics; D001666:Binding Sites, Antibody / Q000235:genetics; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics*; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000378:metabolism; D007145:Immunoglobulin kappa-Chains / Q000235:genetics* / Q000378:metabolism; D007146:Immunoglobulin lambda-Chains / Q000235:genetics* / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000378:metabolism; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000378:metabolism; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics*
D007135:Immunoglobulin Variable Region; D007145:Immunoglobulin kappa-Chains; D007146:Immunoglobulin lambda-Chains; D009363:Neoplasm Proteins; D011947:Receptors, Antigen, B-Cell